Rhodium/Chiral Diene Complexes in the Catalytic Asymmetric Arylation of β‑Pyrazol-1-yl Acrylates

The asymmetric conjugate addition of arylboronic acids to substituted and unsubstituted β-pyrazol-1-yl (<i>E</i>)-<i>tert</i>-butyl acrylates <b>4</b> catalyzed by 5 mol % of the Rh­(I)/diene <b>2a</b> catalyst provided the corresponding addition products in 44–98% yield and 91–>99.5% ee. The method was applied to the formal synthesis of (3<i>S</i>)-3-aryl-3-(pyrazol-1-yl)­propanoic acid <b>1b</b> with agonistic activity toward the human GPR40 G-protein coupled receptor

β‑Selective <i>C</i>‑Arylation of Diisobutylaluminum Hydride Modified 1,6-Anhydroglucose: Synthesis of Canagliflozin without Recourse to Conventional Protecting Groups

The β-selective phenylation of benzyl and boronate protected 1,6-anhydroglucose and the direct phenylation of unprotected 1,6-anhydroglucose (<b>10</b>), pretreated with <i>i</i>-Bu₂AlH, <i>i</i>-Bu₃Al, Et₃Al, Me₃Al, or <i>n</i>-octyl₃Al, with triphenylalane or aryl­(chloro)­alanes is reported. The utility of the unprotected version of the method is demonstrated by the synthesis of the SGLT2 inhibitor, canagliflozin (<b>1a</b>), from commercially available <b>10</b> in one C–C bond-forming step. This approach circumvents the need for conventional protecting groups, and therefore no formal protection and deprotection steps are required

β‑Selective <i>C</i>‑Arylation of Silyl Protected 1,6-Anhydroglucose with Arylalanes: The Synthesis of SGLT2 Inhibitors

The stereoselective arylation of hydroxy protected 1,6-anhydro-β-d-glucose with arylalanes to provide β-<i>C</i>-arylglucosides is reported. Modification of triarylalanes, Ar₃Al, with strong Brønsted acids (HX) or AlCl₃ produced more reactive arylating agents, Ar₂AlX, while the incorporation of alkyl dummy ligands into the arylating agents was also viable. Me₃Al and <i>i</i>-Bu₂AlH were found useful in the <i>in situ</i> blocking of the C3-hydroxyl group of 2,4-di-<i>O</i>-TBDPS protected 1,6-anhydroglucose. The utility of the method was demonstrated by the synthesis of the SGLT2 inhibitor, canagliflozin

Rh(I)-Catalyzed 1,4-Conjugate Addition of Alkenylboronic Acids to a Cyclopentenone Useful for the Synthesis of Prostaglandins

An efficient and <i>trans</i>-diastereoselective Rh­(I)-catalyzed 1,4-conjugate addition reaction of alkenylboronic acids and a homochiral (<i>R</i>)-4-silyloxycyclopentenone useful for the synthesis of derivatives of prostaglandins E and F is described for the first time. The reaction functions under mild conditions and is particularly rapid (≤6 h) under low power (50 W) microwave irradiation at 30 °C in MeOH in the presence of a catalytic amount of KOH. Under these conditions, 3 mol % of [RhCl­(COD)]₂ is typically required to produce high yields. The method also functions without microwave irradiation at 3 °C in the presence of a stoichiometric amount of KOH. Under these conditions, only 1.5 mol % of [RhCl­(COD)]₂ is needed, but the reaction is considerably slower. The method accepts a range of aryl- and alkyl-substituted alkenylboronic acids, and its utility has been demonstrated by the synthesis of PGF_2α (dinoprost) and tafluprost

Rhodium-Catalyzed Asymmetric Addition of Arylboronic Acids to β‑Nitroolefins: Formal Synthesis of (<i>S</i>)‑SKF 38393

An efficient enantioselective addition of an array of arylboronic acids to various β-nitrostyrenes catalyzed by a novel and reactive rhodium–diene catalyst (S/C up to 1000) was developed, providing β,β-diarylnitroethanes in good to high yields (62–99%) with excellent enantioselectivities (85–97% ee). The method was extended to 2-heteroarylnitroolefins and 2-alkylnitroolefins similarly providing the desired products with high enantioselectivities and yields. The usefulness of this method was demonstrated in the formal synthesis of the enantiomer of the dopamine receptor agonist and antagonist, SKF 38393

Enantioselective and Rapid Rh-Catalyzed Arylation of <i>N</i>‑Tosyl- and <i>N</i>‑Nosylaldimines in Methanol

Enantiomerically enriched tosyl-protected diarylmethylamines were rapidly prepared by the asymmetric addition of arylboronic acids to <i>N</i>-tosylaldimines under mild conditions in the presence of a catalyst prepared in situ from Rh­(I) and a chiral diene ligand. This methodology offers access to diarylmethylamines in good yields with excellent chiral purity at room temperature using MeOH as a solvent and NEt₃ as a base. Its synthetic utility was demonstrated by the preparation of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (<b>14</b>), an antagonist of the <i>N</i>-methyl-d-aspartate (NMDA) receptor

Enantioselective and Rapid Rh-Catalyzed Arylation of <i>N</i>‑Tosyl- and <i>N</i>‑Nosylaldimines in Methanol

Enantiomerically enriched tosyl-protected diarylmethylamines were rapidly prepared by the asymmetric addition of arylboronic acids to <i>N</i>-tosylaldimines under mild conditions in the presence of a catalyst prepared in situ from Rh­(I) and a chiral diene ligand. This methodology offers access to diarylmethylamines in good yields with excellent chiral purity at room temperature using MeOH as a solvent and NEt₃ as a base. Its synthetic utility was demonstrated by the preparation of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (<b>14</b>), an antagonist of the <i>N</i>-methyl-d-aspartate (NMDA) receptor

A Stereoselective Process for the Manufacture of a 2′-Deoxy-β‑d‑Ribonucleoside Using the Vorbrüggen Glycosylation

A practical and scalable process for the manufacture of cladribine (<b>1</b>) is described. Vorbrüggen glycosylation of doubly silylated 2-chloroadenine <b>2</b> with protected 1-<i>O</i>-acetyl-2-deoxy-α,β-d-ribofuranose <b>3</b> under reversible conditions in the presence of 20 mol % triflic acid in a solvent that selectively precipitated the desired β-anomer β-<b>4a</b> whilst leaving the unwanted α-anomer α-<b>4a</b> in solution to isomerise allowed good overall stereoselectivity with exclusive regioselectivity. An aging step allowed anomerisation of α-<b>4a</b> to β-<b>4a</b>, thereby improving the isolable yield of the β-anomer. Direct filtration of the product mixture without a catalyst quench or aqueous workup furnished the crude β-anomer β-<b>4a</b> in good yield (up to 68%) and purity (>95% by HPLC) with no regioisomers detected and only ∼1–3% (by HPLC) of the undesired α-anomer. Deprotection of the crude, unpurified intermediate β-<b>4a</b> followed by recrystallisation provided drug-grade cladribine (<b>1</b>). The process includes three isolation steps and was demonstrated on kilogram scales using cGMP providing 99.8–99.9% pure cladribine in up to an overall 43% yield based on 2-chloroadenine (<b>5</b>). In contrast to previous methods, column chromatography and/or bulky directing groups were not required in the glycosylation step, a high pressure vessel was not needed in the deprotection step, and only one dedicated recrystallisation step was necessary

The Manufacture of a Homochiral 4‑Silyloxycyclopentenone Intermediate for the Synthesis of Prostaglandin Analogues

A process is described for the synthesis of kilogram quantities of homochiral 4-silyloxycyclopentenone (<i>R</i>)-<b>1</b>, a key intermediate useful for the synthesis of a plurality of prostaglandin analogue drugs. Cyclopentenone (<i>R</i>)-<b>1</b> was synthesized in 14 isolated steps from furfural. Key steps in the synthesis include a Wittig reaction, Piancatelli rearrangement, and an enzymatic resolution featuring in situ recycling of the undesired enantiomer furnishing the desired homochiral alcohol in ≥99.5% ee. As a retort to the unsatisfactory coformation of about 8% at best of the <i>trans</i>-olefin in the Wittig reaction, a change to the order of several steps and the identification of a recrystallisable, amine salt derivative, <b>2</b>, allowed the unwanted isomer to be controlled to as low as 0.2%